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Objectives Recombinant activated factor VIIa (rVIIa) is used off-label for refractory bleeding after cardiac surgery. This study reviewed the indications, usage rates, and complications of rVIIa. Design A retrospective case-control observational study. Setting A single quaternary pediatric hospital. Participants All children undergoing cardiac surgery with cardiopulmonary bypass over a three-year period. Interventions Administration of rVIIa as rescue therapy for refractory bleeding after weaning from cardiopulmonary bypass. Measurements and Main Results Onethousand, five hundred fifteen cardiopulmonary bypass procedures were reviewed. Patients receiving rVIIa were each matched to two control patients by age, procedure type, and bypass time. Data collected included weight, crossclamp time, anticoagulant and antifibrinolytic dose, return to the operating room for bleeding, thrombotic events, and extracorporeal membrane oxygenation (ECMO) circuit interventions. Forty-two patients received rVIIa (2.8%). Major systemic thrombotic complications were observed in 19% (controls 12.5%) of patients; 80% of recombinant factor VIIa patients requiring postoperative ECMO had interventions for circuit thrombosis (controls 31.25%); 4.76% of rVIIa recipients required reexploration for intractable bleeding (controls 1.39%). Conclusions This study added to understanding regarding the use of recombinant factor VIIa in pediatric cardiac surgery and reported increased thrombotic complications, especially for children who progress to ECMO. Prospective studies to better understand the pathophysiology of coagulopathy and hemorrhage in pediatric cardiac surgery and the role of hemostatic agents, such as rVIIa, are required.

Several drugs that reduce functional levels of the plasma protease zymogen factor XI (FXI), or that inhibit its activated form (FXIa), are being evaluated as treatments to prevent thrombosis. Based on the observation that individuals with inherited FXI deficiency have a relatively mild bleeding disorder, it is anticipated that therapeutic FXI(a) inhibitors will have a smaller impact on hemostasis than anticoagulants targeting thrombin or factor Xa. However, even if FXI(a) inhibitors are determined to be safer than currently used anticoagulants, some patients on these drugs will experience abnormal bleeding or require emergent surgery. Strategies for dealing with such situations are required. Treatment with antifibrinolytic agents and low doses of recombinant factor VIIa effectively prevent abnormal bleeding in FXI-deficient patients with alloantibody inhibitors to FXI who undergo surgery. We propose that a similar strategy can be used for patients on therapeutic FXI(a) inhibitors who are bleeding or require invasive procedures.

Pulmonary complications post-hematopoietic stem cell transplantation (HSCT) such as diffuse alveolar hemorrhage (DAH) can occur in 2% to 14% of HSCT patients and have a mortality greater than 80%. Diffuse alveolar hemorrhage is considered to be an inflammatory response; therefore, HSCT patients are primarily treated with different types of systemic corticosteroids with varying dosages. Other treatments currently reported in the literature in conjunction with corticosteroids include aminocaproic acid, recombinant factor VIIa (rFVIIa), and etanercept. This review highlights appropriate frontline and adjunctive treatment options for HSCT patients with DAH and outcomes for each intervention. To perform the review, the PubMed database was searched from inception through March 19, 2021, to identify potential studies using the search terms DAH and HSCT, DAH and hematopoietic cell transplant (HCT), DAH and stem cell, lung injury and HSCT, and lung injury and HCT. When applicable, references from articles identified in the search were also reviewed for inclusion. Much of the data identified were limited to retrospective cohort studies and case series. Based on the data available, the treatment approach should consist of corticosteroid therapy with a suggested methylprednisolone dose of 250 mg daily followed by a 50% taper every 3 days. Intrapulmonary administration of rFVIIa and intravenous administration of aminocaproic acid could be considered as adjunctive agents in those patients who do not promptly respond to corticosteroid therapy. Due to a lack of data specific to HSCT patients who develop DAH and the risk of infectious complications, etanercept should be avoided. Future studies should be designed as randomized controlled trials and examine the use of adjunctive therapies in the upfront setting for HSCT patients with DAH.

Introduction Haemophilia patients with inhibitors often require a bypassing agent (BPA) for bleeding episode management. Eptacog beta (EB) is a new FDA-approved recombinant activated human factor VII BPA for the treatment and control of bleeding in haemophilia A or B patients with inhibitors (≥12 years of age). We describe here the EB safety profile from the three prospective Phase 3 clinical trials performed to date. Aim To assess EB safety, immunogenicity and thrombotic potential in children and adults who received EB for treatment of bleeding and perioperative care. Methods Using a randomized crossover design, 27 subjects in PERSEPT 1 (12-54 years) and 25 subjects in PERSEPT 2 (1-11 years) treated bleeding episodes with 75 or 225 μg/kg EB initially followed by 75 μg/kg dosing at predefined intervals as determined by clinical response. Twelve PERSEPT 3 subjects (2-56 years) received an initial preoperative infusion of 75 μg/kg (minor procedures) or 200 μg/kg EB (major surgeries) with subsequent 75 μg/kg doses administered intraoperatively and post-operatively as indicated. Descriptive statistics were used for data analyses. Results Sixty subjects who received 3388 EB doses in three trials were evaluated. EB was well tolerated, with no allergic, hypersensitivity, anaphylactic or thrombotic events reported and no neutralizing anti-EB antibodies detected. A death occurred during PERSEPT 3 and was determined to be unlikely related to EB treatment by the data monitoring committee. Conclusion Results from all three Phase 3 trials establish an excellent safety profile of EB in haemophilia A or B patients with inhibitors for treatment of bleeding and perioperative use.

Introduction Surgical procedures in persons with haemophilia A or B with inhibitors (PwHABI) require the use of bypassing agents (BPA) and carry a high risk of complications. Historically, only two BPAs have been available; these are reported to have variable responses. Aim To prospectively evaluate the efficacy and safety of a new bypassing agent, human recombinant factor VIIa (eptacog beta) in elective surgical procedures in PwHABI in a phase 3 clinical trial, PERSEPT 3. Methods Subjects were administered 200 µg/kg (major procedures) or 75 µg/kg eptacog beta (minor procedures) immediately prior to the initial surgical incision; subsequent 75 µg/kg doses were administered to achieve postoperative haemostasis and wound healing. Efficacy was assessed on a 4-point haemostatic scale during the intra- and postoperative periods. Anti-drug antibodies, thrombotic events and changes in clinical/laboratory parameters were monitored throughout the perioperative period. Results Twelve subjects underwent six major and six minor procedures. The primary efficacy endpoint success proportion was 100% (95% CI: 47.8%-100%) for minor procedures and 66.7% (95% CI: 22.3%-95.7%) for major procedures; 81.8% (95% CI: 48.2%-97.7%) of the procedures were considered successful using eptacog beta. There was one death due to bleeding from a nonsurgical site; this was assessed as unlikely related to eptacog beta. No thrombotic events or anti-eptacog beta antibodies were reported. Conclusion Two eptacog beta dosing regimens in PwHABI undergoing major and minor surgical procedures were well-tolerated, and the majority of procedures were successful based on surgeon/investigator assessments. Eptacog beta offers clinicians a new potential therapeutic option for procedures in PwHABI.

Outcomes following administration of very-low-dose recombinant activated factor VIIa (vld-rFVIIa) for cardiac surgical bleeding remain debatable. We sought to determine the association of vld-rFVIIa and adverse surgical outcomes. Retrospective, cohort matching of patients undergoing cardiac surgery who received vld-rFVIIa (median 13.02 μg/kg) for perioperative bleeding were matched to cardiac surgical patients who had bleeding and received standard of care for bleeding without Factor VIIa administration. Of the 362 matched patients (182 in each group), patients who received rFVIIa required significantly less red blood cell transfusions [median 3 units (range 0--60, IQR = 4 units) versus 4 units (range 2-34, IQR = 4 units); P = 0.0004], decreased length of hospital stay (median 8 versus 9 days; P = 0.0158) and decreased renal risk (P

Background Haemophilia A is an X-linked genetic condition which manifests itself mainly in male children in the first 2 years of life, during gross motor skill development. This disorder is rare in females. The clinical manifestation of severe haemophilia in preterm infants poses a great challenge to the therapeutic team. As extreme prematurity is linked to an increased risk of central nervous system or gastrointestinal bleeding, a well-informed and balanced treatment from the first days of life is crucial to prevent long-term damage. Haemophilia is most commonly caused by inheriting defective genes, and can also be linked to skewed X inactivation and Turner syndrome. The coincidental occurrence of haemophilia A and Turner syndrome is extremely rare, with only isolated cases described to date. Hence, a multidisciplinary approach is needed. Case presentation The authors report on a preterm girl (gestational age 28 weeks) diagnosed with haemophilia and Turner syndrome. The first manifestation of haemophilia was prolonged bleeding from injection sites on the second day of life. Indeterminate aPTT and factor VIII level Conclusions Haemophilia should always be considered in the differential diagnosis of prolonged bleeding, even in patients with a negative family history. In the case of coinciding atypical phenotypic features, further diagnostics for another genetic disease are recommended. Infant care should follow current care standards, while considering certain individual features.

Patients with cirrhosis frequently have complex alterations in their hemostatic system. Although routine diagnostic tests of hemostasis in cirrhosis (platelet count, prothrombin time, fibrinogen level) are suggestive of a bleeding tendency, it is now widely accepted that these tests do not reflect hemostatic competence in this population. Rather, patients with cirrhosis appear to have a rebalanced hemostatic system with hypercoagulable elements. Therefore, routine correction of hemostasis laboratory values, for example by fresh frozen plasma or platelet concentrates, with the aim to avoid spontaneous or procedure‐related bleeding is not indicated as is outlined in recent clinical guidance documents. However, little guidance on how to manage patients with cirrhosis that are actively bleeding is available. Here we present three common bleeding scenarios, variceal bleeding, post‐procedural bleeding and bleeding in a critically ill cirrhosis patient, with specific management suggestions. As patients with cirrhosis generally have adequate hemostatic competence and as bleeding complications may be unrelated to hemostatic failure, prohemostatic therapy is not the first line of management in bleeding patients with cirrhosis, even in the presence of markedly abnormal platelet counts and/or prothrombin times. We provide a rationale for the restrictive approach to prohemostatic therapy in bleeding patients with cirrhosis.

Acquired hemophilia due to inhibitor antibodies to factor VIII (FVIII) is a very rare entity in neonatal period. Maternal IgG antibodies may cross the placenta and can cause life-threatening hemorrhages in newborns. Here, we represent a newborn who diagnosed as a transplacental acquired hemophilia A. A very high titer of inhibitor level (320 Nijmegen-Bethesda unit) was detected in plasma due to transplasental transfer in this case. According to the best of our knowledge the baby had the highest inhibitor level in neonatal period in the literature. Bleeding complications including intracranial hemorrhage secondary to this condition were reported before. Therefore, to prevent possible life complications, prophylactic recombinant FVIIa was administered in the presenting case and any bleeding event was not observed during follow-up. In conclusion, using prophylactic recombinant FVIIa in newborns is a safe choice for transplacental acquired hemophilia A.

BACKGROUND: In vitro efficacy of pro- and antihemostatic drugs is profoundly different in patients with compensated cirrhosis and in those who have cirrhosis and are critically ill.OBJECTIVES: Here we assessed the efficacy of pro- and anticoagulant drugs in plasma of patients undergoing hepato-pancreato-biliary (HPB) surgery, which is associated with unique hemostatic changes.METHODS: We performed in vitro analyses on blood samples of 60 patients undergoing HPB surgery and liver transplantation: 20 orthotopic liver transplantations, 20 partial hepatectomies, and 20 pylorus-preserving pancreaticoduodenectomies. We performed thrombin generation experiments before and after in vitro addition of fresh frozen plasma (FFP), prothrombin complex concentrate (PCC), recombinant factor VIIa (rFVIIa), low molecular weight heparin (LMWH), unfractionated heparin, dabigatran, and rivaroxaban.RESULTS: We showed that patients undergoing HPB surgery are in a hypercoagulable state by thrombin generation testing. FFP and rFVIIa had minimal effects on thrombin generation, whereas PCC had a more pronounced procoagulant effect in patients compared with controls. Dabigatran showed a more pronounced anticoagulant effect in patients compared with controls, whereas rivaroxaban and LMWH had a decreased anticoagulant effect in patients.CONCLUSION: We demonstrate profoundly altered in vitro efficacy of commonly used anticoagulants, in patients undergoing HPB surgery compared with healthy controls, which may have implications for anticoagulant dosing in the early postoperative period. In the correction of perioperative bleeding complications, PCCs appear much more potent than FFP or rFVIIa, and PCCs may require conservative dosing and caution in use in patients undergoing HPB surgery.

INTRODUCTION: Transfusion therapy in hemorrhaging trauma patients is associated with the development of thromboembolic events. It is unknown whether current resuscitation strategies, including large volumes of plasma and early administration of procoagulant therapy, increases this risk. METHODS: A systematic search was conducted in MEDLINE, PubMed, and Embase. Studies were screened by two independent reviewers and included if they reported on thromboembolic events in patients with severe trauma (injury severity score ≥16) who received transfusion of at least 1 unit of red blood cells. The ratio by which blood products were transfused, as well as use of procoagulant or antifibrinolytic medication, was recorded. RESULTS: A total of 40 studies with 11.074 bleeding trauma patients were included, in which 1.145 thromboembolic events were reported, yielding an incidence of 10% thromboembolic events. In studies performing routine screening for thromboembolic complications, the incidence ranged from 12% to 23%. The risk of thromboembolic events was increased after administration of tranexamic acid (TXA; odds ratio [OR], 2.6; 95% confidence interval [CI], 1.7-4.1; p < 0.001) and fibrinogen concentrate (OR, 2.1; 95% CI, 1.0-4.2; p = 0.04). Blood product ratio, the use of prothrombin complex concentrate or recombinant factor VIIa were not associated with thromboembolic events. CONCLUSION: This systematic review identified an incidence of thromboembolic events of 10% in severely injured bleeding trauma patients. The use of TXA and fibrinogen concentrate was associated with the development of thromboembolic complications.

The direct oral anticoagulants targeting coagulation factor Xa or thrombin are widely used as alternatives to vitamin K antagonists in the management of venous thromboembolism and nonvalvular atrial fibrillation. In case of bleeding or emergency surgery, reversal agents are helpful to counteract the anticoagulant therapy and restore hemostasis. While idarucizumab has been established as an antidote for the direct thrombin inhibitor dabigatran, reversal strategies for the direct factor Xa inhibitors have been a focal point in clinical care over the past years. In the absence of specific reversal agents, the off-label use of (activated) prothrombin complex concentrate and recombinant factor VIIa have been suggested as effective treatment options during inhibitor-induced bleeding complications. Meanwhile, several specific reversal agents have been developed. In this review, an overview of the current state of nonspecific and specific reversal agents for the direct factor Xa inhibitors is provided, focusing on the biochemistry and mechanism of action and the preclinical assessment of newly emerging therapies.

In emicizumab prophylaxis, the concomitant therapy using bypassing agents (BPAs) is required for breakthrough bleeding and invasive procedures with attention to thrombotic complications. To predict coagulant effects of BPAs in emicizumab-treated patients with haemophilia A (PwHA) with inhibitor (PwHAwI), blood samples from emicizumab-treated PwHAwI (n = 8) and PwHA without inhibitor (n = 2) in phase 1/2 and HAVEN 1 study, spiked with activated prothrombin complex concentrates (aPCC) or recombinant factor VIIa (rFVIIa) ex vivo, and blood samples from emicizumab-treated PwHAwI-receiving BPAs were analysed by Ca2+ -triggered rotational thromboelastometry (ROTEM) and ellagic acid/tissue factor-triggered clot waveform analysis (CWA). Spiked aPCC, corresponded to 10-100 U/kg, markedly shortened ROTEM parameters beyond the normal range, while spiked rFVIIa, corresponded to 90-270 μg/kg, shortened them within near-normal range. Each of the spiked BPA-improved adjusted maximum coagulation velocity of CWA to within or near the normal range. In blood samples at post-infusion of aPCC (44-73 U/kg) or rFVIIa (79-93 μg/kg), the parameters of both assays improved to approximately the normal range. Taken together, ex vivo results of spiking tests in ROTEM and CWA, except aPCC spiking test in ROTEM, were relatively consistent with in vivo ones, and could usefully predict the coagulant effects of concomitant bypassing therapy for emicizumab-treated PwHAwI.

A 4-month-old girl initially presented to the pediatric ICU at 9 days old with multiorgan failure and cerebellar hemorrhage secondary to disseminated enteroviral infection and was eventually listed for liver transplant. Due to severe coagulopathy, she developed a hemothorax after line placement. Despite operative exploration and multiple recombinant factor VIIa doses, massive bleeding continued. The bleeding was finally controlled with thromboelastography-targeted platelet and cryoprecipitate transfusion in addition to four-factor prothrombin complex concentrate administration. This management strategy was invaluable in controlling bleeding from an iatrogenic cause.

Background: Damage control resuscitation forms the cornerstone of management in trauma surgery. Several blood products have been widely used for preoperative transfusions prior to emergency surgeries and for hemorrhage control in trauma. Prothrombin complex concentrate (PCC) is now being introduced as an essential component of damage control resuscitation. Summary: We did a comparative descriptive analysis of several single and multi-institutional clinical trials and retrospective cohort studies. The primary focus of these studies was a comparison between PCC and other transfusion modalities including recombinant factor VIIa, fresh-frozen plasma, and fibrinogen based on several vital parameters. The parameters included rapid international normalized ratio reversal, hospital length of stay, cost-effectiveness, mortality rate, and rate of thromboembolic complications. Key Points: Although still awaiting its approval from the FDA for use in traumatic coagulopathy, 4-factor PCC has shown far more convincing results in contrast to former transfusion modalities, even 3-factor PCC. However, more prospective extensive clinical trials on national levels are needed to compare its effectiveness to 3-factor PCC and gather promising recognition in the trauma care fraternity.

Introduction Recombinant FVIIa (rFVIIa) is widely used to manage bleeding risk during and after surgery in patients with haemophilia complicated by inhibitors. In the postoperative period, rFVIIa must be delivered frequently and regularly to maintain haemostasis, considering its short half-life. Preparation and manual administration of bolus doses of rFVIIa at regular intervals may place a strain on available nursing resources. A programmable mini-pump may offer an approach to facilitate regular administration of bolus doses of rFVIIa at specified intervals. Aim To investigate if a mini-pump is a practical and effective way to deliver rFVIIa in the postoperative period. Methods It was first necessary to establish that rFVIIa remains stable and sterile in the mini-pump reservoir for an extended period. Four days after loading the mini-pump under sterile conditions no evidence of bacterial or fungal growth was observed and in vitro procoagulant activity of rFVIIa remained stable. The mini-pump was used to deliver rFVIIa as bolus doses to two patients with inhibitors who had undergone surgery. Nurses were asked to report their satisfaction with the use of the mini-pump using a specific questionnaire. Results Haemostasis was evaluated as excellent in both cases; nurses were satisfied with use of the mini-pump. Conclusion This pilot study shows that intermittent delivery of rFVIIa at fixed intervals using an automated mini-pump offers accurate and reliable administration in the postoperative setting. This approach may reduce burden on nursing staff, potentially minimize the risk of human error and avoid delay in administration of rFVIIa.

Prolonged prothrombin time and thrombocytopenia are common in patients with cirrhosis. These parameters do not reflect the overall hemostatic rebalance or bleeding risk in the periprocedural setting; however, attempts to correct these parameters remain frequent. We review the literature on periprocedural bleeding risk, bleeding risk factors, and the risk and benefits of hemostatic interventions in patients with cirrhosis. We provide guidance recommendations on evaluating bleeding risk in this patient group and management of hemostatic abnormalities in the periprocedural setting.

INTRODUCTION Since the approval of emicizumab, a bispecific, factor VIII-mimetic antibody, for use in persons with congenital haemophilia A in 2018, there have been increasing case reports and case series of off-label use of emicizumab in other bleeding disorders, including acquired haemophilia A (AHA) and von Willebrand disease (VWD). AIM We conducted a scoping review on the use of emicizumab in AHA and VWD, focusing on the clinical presentation and outcomes. METHODS We conducted a comprehensive search in PubMed, EMBASE and Scopus up to July 15, 2021. The following criteria were applied to the studies identified in the initial search: patients had a diagnosis of AHA or VWD; and the study reported on the clinical outcome of emicizumab use. RESULTS Seventeen studies were included in the final review for a total of 41 patients (33 AHA, eight type 3 VWD). The majority of AHA patients and all type 3 VWD patients were started on emicizumab for active/recurrent bleeds. The dosing regimen of emicizumab used varied significantly in AHA patients. All patients had a clinical response to emicizumab use. One AHA patient developed a stroke on emicizumab use in association with concomitant recombinant FVIIa use for surgery. Data on adverse events from emicizumab use were not specifically reported in 24.4% of patients (four AHA, six type 3 VWD). CONCLUSION Based on published case reports and case series, emicizumab appears to be an effective haemostatic therapy for AHA and VWD. Larger confirmatory clinical trials are needed to confirm these findings.

A low-dose rituximab regimen for first-line treatment of acquired haemophilia A. INTRODUCTION Acquired haemophilia A (AHA) is a rare disease caused by the development of autoantibodies against FVIII. Diagnosis involves confirmation of FVIII deficiency and the presence of an inhibitor via the Bethesda assay. Severe bleeding is often managed with bypassing agents such as recombinant factor VII. This is then followed by eradication of the inhibitor with immunosuppression which typically includes a corticosteroid backbone. AIM Review the current management and outcomes of AHA in Queensland, Australia. Determine the incidence, demographics and clinical characteristics of AHA patients. METHODS Retrospective case series of AHA diagnosed between May 2014 and August 2018. Data were derived from the Australian Bleeding Disorders Registry and state-wide pathology database. Data collection proforma was completed by the treating haematologist and reviewed/compiled centrally. RESULTS 24 patients were identified (incidence 1 in 1.27 million). The median age was 76.5 years. Median follow-up was 20 months. Index bleed was atraumatic and skin/soft tissue in the majority of patients. Recombinant FVIIa was the most commonly used haemostatic therapy and effective in 85% of patients. Immunosuppression and steroid usage were uniform. Upfront second agent was used in 75% of patients and was most commonly rituximab. 87.5% of patients achieved a complete remission in a median time of 48 days. Low-dose rituximab was frequently used and equally as efficacious as standard dose. CONCLUSION Immunosuppression with combination therapy, notably rituximab, appears to be non-inferior and has a favourable side effect profile.

Introduction Intracerebral hemorrhage is the deadliest form of stroke. Hematoma expansion, growth of the hematoma between the baseline computed tomography scan and a follow-up computed tomography scan at 24 ± 6 h, predicts long-term disability or death. Recombinant factor VIIa (rFVIIa) has reduced hematoma expansion in previous clinical trials with a variable effect on clinical outcomes, with the greatest impact on hematoma expansion and potential benefit when administered within 2 h of symptom onset. Methods Factor VIIa for Hemorrhagic Stroke Treatment at Earliest Possible Time (FASTEST, NCT03496883) is a randomized controlled trial that will enroll 860 patients at ∼100 emergency departments and mobile stroke units in five countries. Patients are eligible for enrollment if they have acute intracerebral hemorrhage within 2 h of symptom onset confirmed by computed tomography, a hematoma volume of 2 to 60 mL, no or small volumes of intraventricular hemorrhage, do not take anticoagulant medications or concurrent heparin/heparinoids (antiplatelet medications are permissible), and are not deeply comatose. Enrolled patients will receive rFVIIa 80 µg/kg or placebo intravenously over 2 min. The primary outcome measure is the distribution of the ordinal modified Rankin Scale at 180 days. FASTEST is monitored by a Data Safety Monitoring Board. Safety endpoints include thrombotic events (e.g. myocardial infarction). Human subjects research is monitored by an external Institutional Review Board in participating countries. Discussion In the US, FASTEST will be first NIH StrokeNet Trial with an Exception from Informed Consent which allows enrollment of non-communicative patients without an immediately identifiable proxy.

BACKGROUND Bleeding of unknown cause (BUC) and unclassified bleeding disorders (UBD) are increasingly recognized. There is no guidance on diagnosis and management. OBJECTIVES To examine UK haemophilia centre registration patterns and current practice for UBD patients. METHODS In a two-step process, the UK National Haemophilia Database (NHD) was reviewed for registration patterns of UBD patients and a survey of UK haemophilia centers was conducted (January/February 2021) to capture current practice for diagnosis and management of patients with UBD. RESULTS/DISCUSSION Overall, registrations with the NHD for UBD patients has sharply risen from 2012 to 2020 and in 2019 accounted for 2.65% of registered patients. For the survey, the response rate was 52/67 (78%). Practice was widely variable; 35/52 (67%) centers register UBD; among these 35 centers, terminology included UBD (28 centers), undiagnosed bleeding disorder (four centers), and BUC (three centers); 34/52 (65%) centers use a formal bleeding assessment tool. For management of dental extraction and high bleeding risk surgery in a fictional UBD patient we found that tranexamic acid was widely used; however, beyond this a variety of hemostatic products were advised including blood products, recombinant factor VIIa/prothrombin complex concentrate, and desmopressin. There was general consensus (≈90%) on avoiding regional anesthesia in pregnancy, but no agreement on the need for fetal precautions to avoid bleeding at delivery (50% would advise these). There was a disparity of opinion on chemical thromboprophylaxis, and management of patients without prior hemostatic challenges and offspring of these patients. CONCLUSION This study provides a snapshot of current practice and real-world data in this area. Future studies need to address the gaps in evidence.

Background Factor XI (FXI) deficiency is a rare autosomal bleeding disorder. The rarity of spontaneous bleeding and absence of optimal tools to predict the bleeding risk in FXI-deficient patients hamper the standardization of prophylactic treatment enabling them to undergo major surgeries without blood products. Objectives We explored the effectiveness of a single and very low dose of recombinant factor VIIa (rFVIIa) along with tranexamic acid (TXA) as prophylactic treatment for FXI-deficient patients undergoing various types of surgery at various sites of injury. We studied the potential use of thrombin generation (TG) as a surrogate tool for predicting thrombogenicity. Patients and Methods Our cohort consisted of 10 patients with severe FXI deficiency undergoing 12 interventions. Patients received a single dose of 10 to 15 μg/kg rFVIIa at the end of surgery in addition to TXA initiated 2 hours before surgery at the dose of 4 g/day for 3 to 5 days. TG was tested before and 30 minutes after rFVIIa administration. Results All operations were uneventful and none of the patients bled excessively or required blood products. No thrombotic event was reported, and the postoperative hospitalization duration was comparable to that of patients without bleeding disorders. TG performed at the peak of rFVIIa was below the curve of healthy controls, thus confirming that the administered dose was not thrombogenic. Conclusion A single very low dose of rFVIIa along with TXA is a simple and safe treatment to control hemostasis in severe FXI-deficient patients undergoing diverse type of surgical procedure at various sites.

Background Recombinant activated factor VII (rFVIIa; eptacog alfa activated, NovoSeven® , Novo Nordisk A/S) is a bypassing agent used in congenital hemophilia A patients with inhibitors. Emicizumab (Hemlibra® ; F Hoffmann-La Roche Ltd) is a recombinant, humanized, bispecific monoclonal antibody used for routine prophylaxis in patients with congenital hemophilia A with inhibitors. Concomitant use of the hemostatic agents rFVIIa and emicizumab carries a theoretical increased risk of thrombotic complications. Roche and Novo Nordisk collaboratively analyzed all available data on the use of rFVIIa in patients receiving emicizumab prophylaxis in the Study to Evaluate the Efficacy, Safety, and Pharmacokinetics of Prophylactic Emicizumab Versus no Prophylaxis in Hemophilia A Participants With Inhibitors (HAVEN) clinical development program. Objective Obtain further insights into the concomitant clinical use and safety of rFVIIa and emicizumab. Methods The initial individual rFVIIa dose, dosing intervals and cumulative dosing were evaluated in the HAVEN 1, HAVEN 2, and HAVEN 4 trials. All adverse events reported in each of the three trials in patients treated with rFVIIa, including available narratives, were assessed. Results The vast majority of bleeds occurred in HAVEN 1. When rFVIIa was used to treat a bleeding episode, a 100 ± 20 μg/kg dose was used to initiate treatment in the majority of cases. The dosing interval, as well as cumulative dosing were consistent with prescribing information and current practice. No serious adverse events, no thrombotic microangiopathy cases, or thromboembolic events were assessed to be associated with rFVIIa when used in conjunction with emicizumab prophylaxis in the HAVEN trials. Conclusion rFVIIa use in the context of emicizumab prophylaxis does not change the rFVIIa safety profile as described in the product information.

Healthy neonates exhibit a well-functioning haemostatic system despite peculiarities regarding composition of clotting factors and inhibitors as well as impaired platelet aggregation. Thrombocytopenia and severe bleeding events are feared in sick infants. Recombinant factor VIIa (rFVIIa) is a haemostatic agent used as a last resort in neonates with refractory bleedings. Aim of this study was to investigate in-vitro (i) changes in thrombin generation with different platelet counts, (ii) effects of rFVIIa under conditions of thrombocytopenia and (iii) potentially differing dose-response of rFVIIa in cord blood as a surrogate for neonatal blood compared to adult blood. Thrombin generation parameters were observed in cord blood plasma and adult plasma with various platelet counts, with or without addition of rFVIIa, respectively. Low platelet counts did not influence thrombin generation in cord blood in contrast to adult blood. RFVIIa primarily affected lag time throughout all platelet concentrations. Interestingly, peak height was reduced exclusively in cord blood plasma after addition of rFVIIa. No significant differences regarding dose-response were observed between cord blood and adult blood. In contrast to adult blood, thrombocytopenia in cord blood does not significantly influence thrombin generation. Even at very low platelet counts there is enough negatively charged surface to support rFVIIa action in plasma from cord blood and adult blood in-vitro.

Massive hemorrhage protocols (MHP) are critical to standardized delivery of timely, safe, and resource-effective coordinated care for patients with life-threatening bleeding.A standardized MHP survey was sent to all hospitals (n = 150) in Ontario with a transfusion service. This study aim was to determine the proportion of hospitals with an MHP and assess for variability.The overall survey completion rate was 133 of 150 hospitals (89%) (remaining 17 providing negative affirmation that they did not have an MHP). An MHP was in place at 97 of 150 (65%) hospitals (60% of small (5000 red cell units/year) vs. 91% of medium/large). A total of 10 different names of protocols were reported, with "Massive Transfusion Protocol" (68%) predominating. Activation criteria were present in 82 of 97 (85%); commonly activated based on volume of blood loss (70%). Blood work was drawn at the discretion of the physician (37%) or at predefined intervals (31%; majority every 60 min). Common routine laboratory tests performed were CBC (87%) and INR (84%). Fibrinogen testing was available at 88 (66%) of 133 reporting hospitals and part of the standard testing at 73 of 97 (75%) hospitals with an MHP. Median targets of hemostatic resuscitations, stated in the protocol at 49% of hospitals with an MHP, were: platelets50 × 10A third of hospitals lack formal MHPs, with the majority lacking in smaller hospitals. The survey results indicate that there is marked variability in all key aspects of the reported MHPs. This may be due to differences in hospital resources and personnel, lack of supporting evidence to dictate requirements, and differences in knowledge base of the individuals involved in protocol setting.

Introduction Glanzmann thrombasthenia (GT) is a rare bleeding disorder. The disease is caused by the lack or dysfunction of platelet membrane glycoprotein IIb/IIIa (integrin αIIbβ3) which is essential for platelet aggregation. Bleeding episodes are usually managed by platelet transfusions. Recombinant activated factor VII (rFVIIa) is a common adjunct or alternative treatment option. Objective This article evaluates GT patients' response to increasing concentrations of rFVIIa using an ex vivo thrombin generation assay to elaborate the knowledge in which rFVIIa treats a platelet dysfunction for bleeding episodes and preoperative management. Materials and Methods Twenty-four GT patients in a non-bleeding state were enrolled into the study. Thrombin generation was measured in platelet-rich plasma (PRP) in the presence of 0.7 to 7.0 µg/mL rFVIIa. Clinical data of rFVIIa used to treat GT patients' bleeding episodes was collected, and patients' follow-up course was documented. Results Thrombin generation was significantly decreased in GT patients compared with controls. An individual response to rFVIIa spiking was noted in GT patients' PRP. In the majority of patients, a significant improvement in thrombin generation was already demonstrated with low concentrations (0.7 µg/mL) of rFVIIa. Conclusion Thrombin generation is improved in the majority of GT patients following ex vivo spiking with rFVIIa. The magnitude of this improvement is individual and was noted at low concentrations of rFVIIa. There is a need for a prospective clinical trial to find the optimal doses or rFVIIa for treatment of GT patients.

Bypassing agents are presently the standard of care for the treatment of bleeding episodes in patients with hemophilia and high-titer inhibitors and are also used for bleed prevention. Only two bypassing agents are available to patients, and these products trace their lineage to the 1970s (activated prothrombin complex concentrates) and the 1980s (recombinant factor VIIa). Given the limited repertoire of available products, clinicians have relied on experience, empirical observation, registry data and individualized care to improve clinical outcomes on a case-by-case basis. Research over the past two decades has culminated in a greatly improved understanding of human coagulation; resulting from this, new products have been developed that offer treatment options and mechanisms of actions that differ from current bypassing agents. The most advanced in clinical development is emicizumab, a bispecific antibody that mimics the function of FVIIIa in the intrinsic Xase complex and is indicated for once-weekly or every-other-week prophylactic dosing in inhibitor patients. Other non-traditional products in clinical development include fitusiran and antibodies directed against tissue factor pathway inhibitor. As non-factor-based therapies become more widely utilized over time, the use of bypassing agents may be expected to decrease; however, bypassing agents will remain essential for the foreseeable future. As such, clinical development of bypassing agents continues, with some products (e.g. eptacog beta) under regulatory review. In this review we examine the optimal use of bypassing agents and their mechanism of action. We also discuss newer products and how these might theoretically be administered in conjunction with traditional bypassing agents.

Glanzmann thrombasthenia is an inherited disease causing bleeding episodes due to platelet dysfunction. The standard treatment for moderate-severe bleeding is platelet transfusion. Recombinant factor VIIa (rFVIIa) is successfully used in bleeding episodes and invasive procedures. Here, we present a patient with Glanzmann thrombasthenia, whose bleeding episodes could only be controlled by rFVIIa. The patient is a 28 years old male, who has had frequent bleeding episodes unresponsive to local hemostatic agents and tranexamic acid and had an anaphylactoid reaction to platelet transfusion. We started the patient on a low-dose (20 μg/kg) rFVIIa once a week. The patient has no spontaneous bleeding since then. This is the first case report of a Glanzmann thrombasthenia patient on routine prophylaxis with low-dose rFVIIa.

Introduction Cardiovascular events in patients with inherited bleeding disorders are challenging to manage. The risk of bleeding secondary to antithrombotic treatment must be balanced against the risk of thrombosis secondary to haemostatic therapy. Methods Patients with inherited bleeding disorders with coronary artery bypass grafting (CABG), percutaneous coronary intervention (PCI) or atrial fibrillation (AF) from a single centre (2010-2018) are included. Results A total of 11 patients undergoing CABG (n = 3), PCI (n = 5) or with AF (n = 3) and a diagnosis of haemophilia A (n = 8), haemophilia B (n = 1), factor XI deficiency (n = 1) and von Willebrand disease (n = 1) managed by a multidisciplinary team are reported. In patients undergoing CABG, factor levels were normalized for 7-10 days with trough levels of 70-80% with severe patients continuing high-dose factor prophylaxis (trough 20-30%) three weeks post-operatively with daily aspirin. In a patient with mild haemophilia A and an inhibitor, recombinant factor VIIa dosing was monitored with thromboelastometry. For PCI, a 3rd-generation drug-eluting stent with one month of dual antiplatelet therapy in addition to high-dose prophylaxis as needed was preferred. Patients with AF and severe haemophilia did not receive antithrombotic treatment, and a thrombin generation assay was used to guide heparin dosing in mild haemophilia. Conclusion Our experience demonstrates the importance of interdisciplinary communication to identify strategies that decrease the risk of bleeding and thrombosis. The use of extended, increased intensity prophylaxis facilitated antiplatelet therapy. Global assays may help balance the intensity of haemostatic and antithrombotic treatment.

Background The anti‐tissue factor plasma inhibitor monoclonal antibody concizumab is under clinical investigation for subcutaneous prophylaxis of hemophilia A/B (HA/HB) with or without inhibitors. Breakthrough bleeds while on concizumab prophylaxis may be treated with bypassing agents (recombinant activated factor VIIa [rFVIIa] and activated prothrombin complex concentrate [APCC]), or with factor VIII (FVIII) or factor IX (FIX). Objectives To evaluate the effect of combining concizumab with rFVIIa, APCC, rFVIII, and rFIX on thrombin generation (TG) potential. Methods Pooled HA plasma was spiked in vitro with concizumab alone or together with rFVIIa, APCC, or rFVIII. rFVIIa, APCC, and rFVIII were added ex vivo to plasma from HA patients receiving concizumab prophylaxis. Pooled HB plasma was spiked with concizumab alone or together with rFIX. TG potential was measured after initiation with tissue factor. Results Concizumab increased thrombin peak in a concentration‐dependent manner. Adding rFVIIa, APCC, rFVIII, or rFIX caused a further increase in thrombin peak. The effects of concizumab and rFVIIa, APCC, rFVIII, or rFIX were mainly additive, with no or up to maximally ~25% extra effect caused by drug‐‐drug interaction. No strong synergistic effects were observed upon combining concizumab with rFVIIa, APCC, rFVIII, or rFIX. The thrombin peak obtained with 0.5 IU/ml rFVIII or rFIX in the presence of concizumab was on occasion slightly higher, but mostly comparable to the thrombin peak with 1 IU/ml rFVIII or rFIX in the absence of concizumab. Conclusion rFVIIa, APCC, rFVIII, and rFIX enhanced plasma TG potential in the presence of concizumab. Dose levels of concomitant use should be adjusted accordingly to balance potential safety concerns while maintaining the necessary hemostatic effect. Please see the video in the Supplementary Material for an animated summary of the data presented.

Emicizumab reduces bleeding in patients with hemophilia A and inhibitors (PwHA-I). Coagulation potential during the perioperative period in emicizumab-treated PwHA-I undergoing surgery remains to be evaluated. We describe a 14-year-old boy with HA-I receiving emicizumab prophylaxis who experienced arthroscopic synovectomy. He was treated with a bolus infusion of recombinant factor VIIa (rFVIIa; 80 μg/kg) immediately before surgery, and treatment continued at the same dose every 3 h on day 1, every 4 h on day 2, and every 6 h on day 3. Treatment with rFVIIa was discontinued on day 4. No perioperative bleeding or thrombotic events were observed. Coagulation potential throughout the perioperative period was retrospectively assessed with an easy-to-use clot waveform analysis (CWA). Measurements from CWA returned to within or near the normal range, suggesting successful hemostatic management. Coagulation potentials assessed by CWA showed a significant correspondence with those from a thrombin generation assay (TGA) that is already in use. CWA and TGA could both provide useful data for assessing coagulation potential in the perioperative hemostatic management of emicizumab-treated PwHA-I.

Aim: To assess available evidence on the use of rFVIIa in non-orthopaedic surgery including dental surgery in adult patients with congenital haemophilia with inhibitors (PWHI). Methods: A systematic literature search was performed according to a prespecified search string; prespecified criteria were used to select applicable studies including PWHI ≥18 years of age who underwent any non-orthopaedic surgery using rFVIIa. Results: Thirty-three publications met the eligibility criteria, of which 26 publications – including 46 procedures in 44 patients – were selected for the qualitative analysis. Most publications were case reports or case series (21/26). Primary authors assessed rFVIIa as effective in maintaining haemostasis during and after most major surgeries (22/32). rFVIIa dose was mainly on label, with higher doses used in 4 cases, and a lower dose in 1 case. Duration of treatment was mostly 5–10 days (range: 3 days to 1 month post-operatively). Adverse events related to rFVIIa were rare. Conclusions: Assessing non-orthopaedic surgery in this patient population is hampered by a paucity of published data; nevertheless, the current evidence indicates that rFVIIa is effective in achieving haemostasis in haemophilia patients with inhibitors undergoing elective non-orthopaedic or dental surgery. rFVIIa was generally well tolerated in these patients, with thrombotic events occurring rarely. These data, generated to help clinicians manage congenital haemophilia with inhibitors, highlight the need for more systematic reporting of rFVIIa and all other therapeutic agents in non-orthopaedic surgery and dental surgery in patients with congenital haemophilia and inhibitors. (Less)

As perioperative bleeding continues to be a major source of morbidity and mortality in cardiac surgery, the search continues for an ideal hemostatic agent for use in this patient population. Transfusion of blood products has been associated both with increased costs and risks, such as infection, prolonged mechanical ventilation, increased length of stay, and decreased survival. Recombinant-activated factor VII (rFVIIa) first was approved for the US market in 1999 and since that time has been used in a variety of clinical settings. This review summarizes the existing literature pertaining to perioperative rFVIIa, in addition to society recommendations and current guidelines regarding its use in cardiac surgery.

Background:The rate of bleeding complications following arterial switch operation is too low to independently justify a prospective randomised study for benefit from recombinant factor VIIa. We aimed to evaluate factor VIIa in a pilot study.Methods:We performed a retrospective cohort study of patients undergoing arterial switch operation from 2012 to 2017. Nearest-neighbour propensity score matching on age, gender, weight, and associated cardiac defects was used to match 27 controls not receiving recombinant factor VIIa to 30 patients receiving recombinant factor VIIa. Fisher’s exact test was performed to compare categorical variables. Wilcoxon’s rank-sum test was used to compare continuous variables between cohorts.Results:Post-operative thrombotic complications were not associated with factor VIIa administration (Odds Ratio (OR) 0.28, 95% CI 0.005–3.77, p = 0.336), nor was factor VIIa administration associated with any re-explorations for bleeding. No intraoperative transfusion volumes were different between the recombinant factor VIIa cohort and controls. Post-operative prothrombin time (10.8 [10.3–12.3] versus 15.9 [15.1–17.2], p < 0.001) and international normalised ratio (0.8 [0.73–0.90] versus 1.3 [1.2–1.4], p < 0.001]) were lower in recombinant factor VIIa cohort relative to controls.Conclusions:In spite of a higher post-bypass packed red blood cell transfusion requirement, patients receiving recombinant factor VIIa had a similar incidence of bleeding post-operatively. With no difference in thrombotic complications, and with improved post-operative laboratory haemostasis, a prospective randomised study is warranted to evaluate recombinant factor VIIa.

Emicizumab is currently approved to prevent bleeding in patients with congenital hemophilia A with or without neutralizing antibodies (inhibitors) against factor VIII (FVIII). Here, we present a case-based discussion of its potential use in acquired hemophilia A (AHA), a severe bleeding disorder caused by autoantibodies against FVIII. State-of-the-art management is based on bypassing agents (recombinant factor VIIa, activated prothrombin complex concentrate) and recombinant porcine FVIII; immunosuppressive therapy (corticosteroids, rituximab, cyclophosphamide) is used to suppress autoantibody formation. Case reports and one series suggest that emicizumab can reduce the risk of bleeding and the requirement for hemostatic therapy until remission of AHA is achieved. Further, it may allow to postpone the start of immunosuppressive therapy or to use less intense regimens. However, the risk-benefit assessment of emicizumab in AHA is difficult because demographic and clinical characteristics are different compared with congenital hemophilia. Prospective clinical trials are needed before the use of emicizumab can be recommended in AHA.

Background Emicizumab is a bispecific antibody to factor (F) IXa and FX that mimics the FVIIIa cofactor function. Emicizumab prophylaxis markedly decreases bleeding episodes in patients with hemophilia A (PwHAs), irrespective of the presence of FVIII inhibitors. However, thrombotic microangiopathy (TMA) was reported when repeated high doses of activated prothrombin complex concentrates (aPCC) were concomitantly used with emicizumab. Although bypassing agents (BPAs) are vital in the hemostatic treatment for PwHAs with inhibitors, the mechanism of emicizumab-related TMA remains unclear. Aim To assess the risk of excessive thrombus formation associated with BPAs and emicizumab under high shear conditions. Methods Perfusion flow-chamber experiments under high shear conditions were performed using whole blood from PwHAs in the presence of emicizumab without or together with FVIII or BPAs ex vivo. Results Emicizumab (100 μg/mL) added ex vivo to whole blood from PwHAs improved defective thrombus formation in a similar manner to that observed with the addition of recombinant FVIII at the early phase, while FVIII continued to be important at the later stages. aPCC (1.2 U/mL equivalent to 100 U/kg) or recombinant FVIIa (1.1 µg/mL; equivalent to 90 µg/kg) together with emicizumab further promoted platelet interactions and fibrin formation ex vivo but did not induce excessive thrombus formation. Conclusion Emicizumab enhanced thrombin generation at local sites and improved defective hemostasis in whole blood from PwHAs under high shear conditions. Simple concomitant use of BPAs with emicizumab did not mediate excessive thrombus formation and remains an option for hemostatic management of emicizumab-treated PwHAs with inhibitors.

Glanzmann thrombasthenia is a rare congenital thrombocytopathy. The first-line treatment in severe life-threatening bleeding is a transfusion of platelet concentrate or recombinant factor VIIa in the case of platelet transfusion refractoriness. We present the case of a 16-year-old boy with Glanzmann thrombasthenia who was admitted to hospital with severe bleeding into the quadriceps femoris muscle. At the age of 15 years, he was hospitalized again because of chronic bleeding into the right ankle joint, resulting in joint destruction. Here we give a scheme of management and treatment of this patient. Hemostatic therapy followed by radiosynovectomy of the right ankle joint and introduction of secondary preventive treatment with recombinant factor VIIa proved to be efficacious and safe.

Background In hemophilia bypass therapy, a platelet-dependent mechanism is believed to be primarily responsible for recombinant factor VIIa (rFVIIa)'s hemostatic effect. rFVIIa may also possibly interact with other cells through its binding to endothelial cell protein C receptor (EPCR) or cell surface phospholipids. Objectives We aim to investigate the relative contribution of platelet-dependent and platelet-independent mechanisms in rFVIIa-mediated thrombin generation in hemophilic conditions at the injury site. Methods Platelets were depleted in acquired and genetic hemophilia mice using anti-platelet antibodies. The mice were subjected to the saphenous vein injury, and the hemostatic effect of pharmacological concentrations of rFVIIa was evaluated by measuring thrombin generation at the injury site. Results Administration of anti-mouse CD42 antibodies to mice depleted platelets by more than 95%. As expected, hemophilia mice, compared with wild-type mice, generated only a small fraction of thrombin at the injury site. The depletion of platelets in hemophilia mice further reduced thrombin generation. However, when pharmacological doses of rFVIIa were administered to hemophilia mice, substantial amounts of thrombin were generated even in the platelet-depleted hemophilia mice. No differences in thrombin generation were detected among FVIII-/- , EPCR-deficient FVIII-/- , and EPCR-overexpressing FVIII-/- mice depleted of platelets or not. Evaluation of platelets by flow cytometry as well as immunoblot analysis showed no detectable expression of EPCR. Conclusions Our data suggest that pharmacological concentrations of rFVIIa generate thrombin in hemophilia in both platelet-dependent and platelet-independent mechanisms.

Acquired hemophilia A in postoperative patients can cause major bleeding and an accurate diagnosis is required for effective treatment. Standard treatment is costly, difficult to obtain, and takes 4 to 6 weeks to be effective. This article describes a patient successfully treated with recombinant factor VIIa, porcine factor VIII, plasmapheresis, rituximab, and high-dose corticosteroids.

Patient: Male, 91-year-old Final Diagnosis: Acquired hemophilia A Symptoms: Back pain • bleeding • hematuria Medication: — Clinical Procedure: — Specialty: Hematology Objective: Rare disease Background: Acquired hemophilia A (AHA) is a rare autoimmune disease caused by immunoglobulins that bind and inactive factor VIII, thereby predisposing to life-threatening bleeding. Bleeding is typically stabilized by utilizing bypassing agents, such as recombinant factor VIIa (rVIIa). Select case reports have demonstrated the success of alternative prophylaxis for clearance of factor VIII inhibitors through the use of emicizumab, a current FDA approved medication for treatment of congenital hemophilia A. In this case report we present the efficacy of utilizing emicizumab as a prophylactic agent in a patient that was unable to tolerate first-line therapy for prophylaxis. Case Report: A 91-year-old male presented for ongoing hematuria for 5 weeks with prior workup unrevealing. He was given a day’s course of recombinant factor VIIa to stabilize his bleeding and was started on cyclophosphamide and prednisone after a revealing hematological workup including activated partial thromboplastin time (aPTT) >100 seconds and factor VIII inhibitor level of 44 BU/mL. He continued to require VIIa infusions to control his bleeding and was started on emicizumab once stabilized. His bleeding remained controlled and his inhibitor decreased after 6 months of therapy with repeat factor VIII inhibitor level of 1.9 BU/mL. Conclusions: The success of utilizing emicizumab for bleeding prophylaxis in AHA is demonstrated by this patient’s resolution of bleeding. The high frequency of dosing and higher risk for thrombosis with factor VIIa, in conjunction with our patient’s medical history and ease of administration, make emicizumab an ideal agent for bleeding prophylaxis while awaiting clearance of factor VIII inhibitors.

Background: Recombinant factor VIIa (rFVIIa) (Novoseven®) is utilized for the reversal of anticoagulation-associated bleeding and refractory bleeding in cardiac surgery. In August 2015, rFVIIa was transferred from the blood bank to the pharmacy at New York University (NYU) Langone Health. Concordantly, an off-label dosing guideline was developed. The objective of this study was to describe utilization and cost of rFVIIa and assess compliance to our dosing guideline. Methods: We performed a retrospective, observational review of rFVIIa administrations post-implementation of an off-label dosing guideline. All patients who received rFVIIa between September 2015 and June 2017 were evaluated. For each rFVIIa administration, anticoagulation and laboratory values, indications for use, dosing, ordering and administration times, concomitant blood products, and adverse events were collected. Adverse events included venous thromboembolism, stroke, myocardial infarction, and death due to systemic embolism and mortality. The primary endpoint was the utilization of rFVIIa in accordance with the off-label dosing guideline. Secondary endpoints included hemostatic efficacy of rFVIIa, adverse events, blood products administered, and cost-effectiveness of rFVIIa transition to pharmacy. Results: A total of 63 patients [pediatric ( n = 6), adult ( n = 57)] received rFVIIa, with the majority of use for refractory bleeding after cardiac surgery. The utilization of rVIIa decreased after development of the off-label dosing guideline and transition from blood bank to pharmacy. The total incidence of thromboembolic events within 30 days was 19.6%; 17.6% arterial and 2% venous; 70% of patients with an adverse event were over 70 years of age. Use of rFVIIa reduced the median number of units of blood products administered. Conclusion: Administration of rFVIIa for cardiac surgery appears to be effective for hemostasis. Transitioning rFVIIa from the blood bank to pharmacy and implementation of a dosing guideline appears to have reduced utilization. Patients receiving rFVIIa should be monitored for thromboembolic events. Elderly patients may be at higher risk for thromboembolic events.

Trauma-induced coagulopathy (TIC) occurs commonly as a second event following severe injury. We evaluated the effects of fibrinogen, recombinant factor VIIa and factor XIII on blood clotting and fibrinolysis in an in-vitro TIC model. The TIC model included hemodilution, hyperfibrinolysis, acidosis and hypothermia. The extent of clot formation and fibrinolysis was evaluated using rotational thromboelastometry. Clot strength was increased following spiking the TIC blood with either 1.0 mg/ml fibrinogen, 3.0 μg/ml recombinant factor VIIa or 2.0 IU/ml factor XIII. Maximal effect was achieved by all agents in combination approximating the extent of clot formation to those in normal blood. Fibrinolysis was inhibited by factor XIII, while the reduction was stronger using all agents together. When each of the agents used in two times lower concentrations, clot strength was near to threshold. Fibrinogen and factor XIII but not factor VIIa exerted stimulation of clot strength, whereas synergistic effect of fibrinogen and factor XIII was observed. Maximal effect was achieved combining all agents. The antifibrinolytic effect was observed only by co-administration of fibrinogen, factor XIII and factor VIIa. On the basis of our study, we suggest that stimulation of clot formation and inhibition of fibrinolysis may be achieved by combination of FG, rFVIIa an FXIII using each of them at minimal effective concentration. Taken into consideration, multifactorial TIC pathogenesis, this approach may be preferable for improving coagulopathy than separate blood spiking with the essayed factors at high concentrations.

Haemostasis stops bleeding at the site of vascular injury and maintains the integrity of blood vessels through clot formation. This regulated physiological process consists of complex interactions between endothelial cells, platelets, von Willebrand factor and coagulation factors. Haemostasis is initiated by a damaged vessel wall, followed with a rapid adhesion, activation and aggregation of platelets to the exposed subendothelial extra cellular matrix. At the same time, coagulation factors aggregate on the procoagulant surface of activated platelets to consolidate the platelet plug by forming a mesh of cross-linked fibrin. Platelets and coagulation mutually influence each other and there are strong indications that, thanks to the interplay between platelets and coagulation, haemostasis is far more effective than the two processes separately. Clinically this is relevant because impaired interaction between platelets and coagulation may result in bleeding complications, while excessive platelet-coagulation interaction induces a high thrombotic risk. In this review, platelets, coagulation factors and the complex interaction between them will be discussed in detail.

Antithrombin (AT) reduction has been shown to improve thrombin generation (TG) in haemophilia with or without inhibitors. As treatment with bypassing agents (BPAs) may be required in patients with breakthrough bleeding while receiving AT-lowering therapy, we assessed TG in platelet-poor plasma samples from haemophilia patients in the presence of BPA (recombinant activated factor VII [rFVIIa; 1.25 or 2.5 μg mL−1] or activated prothrombin complex concentrate [aPCC; 0.5 or 1 U mL−1]) and AT reduction (anti-AT antibody). Mean ± SEM baseline peak thrombin height was 19.9 ± 4.3 nM in plasma from haemophilia patients (n = 12) and 230.5 ± 9.8 nM in healthy males (n = 24). Reduced AT improved mean peak thrombin height in haemophilia patient plasma to 75.4 ± 17.4 nM. Spiking of 90% AT-reduced haemophilia patient plasma with 2.5 μg mL−1 rFVIIa or 1 U mL−1 aPCC increased the mean peak thrombin height to 82.5 ± 12 nM and 134.8 ± 18.7 nM, respectively. Peak thrombin levels did not exceed the range for healthy volunteers when plasma samples from haemophilia patients with in vitro AT reduction were treated with BPAs, suggesting the potential use of BPAs in conjunction with AT reduction. Further clinical investigations are needed to confirm the safety of this approach.

The development of neutralizing alloantibodies to factor VIII (FVIII), commonly called “inhibitors,” is a major complication of hemophilia A (HA) replacement therapy, occurring in 20% to 30% of patients with severe HA.1-3 In these patients, FVIII replacement becomes inefficient and bleeding events are treated or prevented using bypassing agents (BPAs), which include activated prothrombin complex concentrates (aPCCs) and recombinant factor VIIa (rFVIIa).4,5 BPAs are effective in restoring hemostasis but are often not able to completely normalize thrombin generation, in contrast to FVIII replacement.6 In addition, they have been associated with rare thrombotic adverse events (AEs).7,8 Thus, patients with persistent FVIII inhibitors present increased disease-related morbidity and should be offered immune tolerance induction (ITI). ITI consists of daily infusions of large doses of FVIII given until FVIII inhibitors disappear and FVIII pharmacokinetic parameters normalize.9 Considering suboptimal success rate of such regimens (in the range of 60%-80%),10 inconvenience of repetitive venous access, compliance issues, and cost, there is a major unmet need for therapeutic agents that are associated with effective bleeding control and improved quality of life. Recently, both the US Food and Drug Administration and the European Medicines Agency approved a non–factor replacement therapy, emicizumab, for routine prophylaxis to prevent or reduce the frequency of bleeding episodes in HA adult and pediatric patients with FVIII inhibitors. The purpose of this paper is to bring arguments, based on results obtained from recent studies, that would support the use of prophylaxis with emicizumab independently of ITI.

Essentials Marzeptacog alfa (activated) [MarzAA] is a novel variant of activated human factor VII. A phase 1 dose escalation trial of MarzAA was conducted in subjects with severe hemophilia. MarzAA was safe and tolerated at intravenous doses up to 30 μg kg-1 Data observed support further trials for hemophilia patients with inhibitors to factors VIII/IX. Summary Background Marzeptacog alfa (activated) (MarzAA), a new recombinant activated human factor VII (rFVIIa) variant with four amino acid substitutions, was developed to provide increased procoagulant activity and a longer duration of action in people with hemophilia. Objectives To investigate the safety, tolerability, immunogenicity, pharmacokinetics (PK) and pharmacodynamics (PD) of single ascending intravenous bolus doses of MarzAA in non-bleeding patients with congenital hemophilia A or B with or without inhibitors. Methods This international, phase 1, open-label study (NCT01439971) enrolled males aged 18-64 years with severe hemophilia A or B, with or without FVIII or FIX inhibitors. Subjects were assigned to single-dose MarzAA cohorts (0.5, 4.5, 9, 18 or 30 μg kg-1 ). Blood sampling was performed predose and postdose, and subjects were monitored for 60 days postdose. Safety endpoints included adverse events, vital sign changes, electrocardiograms, laboratory abnormalities, and immunogenicity; secondary endpoints included evaluation of PK and PD. Results Overall, in 25 patients, MarzAA was well tolerated at all dose levels tested, and was not associated with dose-limiting toxicity. No treatment-emergent severe or serious adverse events occurred. MarzAA showed linear dose-response PK across the 4.5-30 μg kg-1 dose range, with a terminal half-life of ⁓ 3.5 h. Dose-dependent shortening of the activated partial thromboplastin time and prothrombin time, and evidence of an increase in peak thrombin as determined with a thrombin generation assay, were observed at all doses. Conclusions MarzAA was tolerated at doses up to 30 μg kg-1 . The safety profile and pharmacological effects observed support further clinical trials for the treatment of hemophilic patients with inhibitors.

The development of neutralizing antibodies is a rare complication of von Willebrand disease treatment. In major surgical procedures for severe forms of the disease, the recognition of ineffective therapy and alternative treatment protocols are lifesaving. We report the case of a 6-year-old girl with type 3 von Willebrand disease in whom inhibitors were sought due to ineffective haemostasis together with lower than expected von Willebrand factor (VWF) recoveries after a surgical procedure. Replacement therapy first with recombinant factor VIIa and then with high doses of recombinant factor VIII in continuous infusion successfully stopped the bleeding. A high level of anti-VWF antibodies was determined by the immunological method. A frameshift mutation associated with premature termination codon (c.2435delC, p.Pro812ArgfsTer31) was determined in our patient. Although the reports on association of this mutation with inhibitor risk are inconsistent, it represents an evidence-based diagnostic and management practice in recognition of high-risk VWF genotype.

BACKGROUND & AIMS: A simultaneous decline in pro- and anticoagulant drivers in patients with liver diseases results in a "rebalanced" haemostatic system, even in acutely ill patients. Nevertheless, both bleeding and thrombotic events are common. Here, we explored efficacy of pro- and antihaemostatic strategies in compensated and acutely ill cirrhotics which may be unpredictable given the profound haemostatic changes.METHODS: We tested the effects in vitro of the addition of clinically relevant doses of commonly used pro- and antihaemostatic strategies in plasma from healthy individuals (n = 30) and patients with compensated (n = 18) and acutely decompensated cirrhosis (n = 18), and acute-on-chronic liver failure (n = 10). We used thrombin generation tests and fibrin clot permeability assays to assess potency of various approaches.RESULTS: Fresh frozen plasma and recombinant factor VIIa modestly increased thrombin generation (10%-20%). Prothrombin complex concentrate increased thrombin generation two-fold in controls and 2-4-fold in patients. Clot permeability decreased after addition of fibrinogen concentrate by 51% in controls and by 50%-60% in patients. Low molecular weight heparin decreased thrombin generation by 18% in controls and by 23%-54% in patients. Similarly, dabigatran decreased thrombin generation by 33% in controls and by 47%-100% in patients. In contrast, rivaroxaban decreased thrombin generation by 55% in controls, but only by 11%-38% in patients.CONCLUSIONS: These in vitro data suggest little prohaemostatic effect of fresh frozen plasma and recombinant factor VIIa in acutely ill cirrhotics, whereas prothrombin complex concentrate and fibrinogen concentrate clearly improved haemostasis. Furthermore, our data suggest the requirement for dose adjustments of commonly used anticoagulants in these patients.

Background In 2010, the U.S. Food and Drug Administration (FDA) approved dabigatran as the first non-warfarin oral anticoagulant for use in the United States. At the time of FDA approval, there was no antidote or effective treatment for dabigatran-induced hemorrhage. In 2015, the FDA approved idarucizumab for the treatment of dabigatran-induced hemorrhage. The purpose of this clinical practice statement is to evaluate the role of select reversal agents in the management of patients with dabigatran-associated bleeding. Methods A PubMed literature review was completed to identify studies that investigated the role of reversal agents in the management of emergency department patients with dabigatran-associated hemorrhage. Articles included were those published in the English language between January 2010 and January 2017, enrolled human subjects, and limited to the following types: randomized controlled trials, prospective trials, meta-analyses, and retrospective cohort studies. Review articles, case series, and case reports were not included in this review. All selected articles then underwent a structured review by the authors. Results Six hundred fifty-two articles were identified in the search. After use of predetermined inclusion and exclusion criteria, six articles were selected for structured review. Conclusion The clinical efficacy of activated prothrombin complex concentrates, idarucizumab, and recombinant factor VIIa remains unclear until further research is performed. Activated prothrombin complex concentrates, idarucizumab, and recombinant factor VIIa may be considered in patients with serious bleeding from dabigatran, after careful consideration of possible benefits and risks.

Objective: To determine the pharmacological treatment methods available to anemic Jehovah’s Witnesses (JW). Data Sources: MEDLINE and PubMed were searched from inception through February 2018 using the search terms Jehovah’s Witnesses, treatment, erythropoietin, hemoglobin-based oxygen carrier, Sanguinate, Hemopure, bleeding, and anemia. Study Selection and Data Extraction: All clinical trials, cohort studies, case-control studies, and observational trials involving pharmacotherapy in anemic JW patients were evaluated. Case reports and bibliographies were also analyzed for inclusion. Data Synthesis: Two studies involving the use of erythropoietin (EPO) and one study involving recombinant factor VIIa were included. Information was also included from other pharmacotherapeutic modalities that had case report data only. Current published evidence is limited with regard to evidence-based management of JW patients. High-dose EPO, intravenous iron supplementation, and hemostatic agents have demonstrated good clinical outcomes in case reports. EPO doses as high as 40 000 units daily have been advocated by some experts; however, pharmacokinetic studies do not support dose-dependent effects. Hemoglobin-based oxygen carriers (HBOCs) are currently not Food and Drug Administration approved. They are available through expanded access programs and may represent a lifesaving modality in the setting of severe anemia. Conclusions: There are currently not enough data to make definitive recommendations on the use of pharmacological agents to treat severe anemia in the JW population. Further evidence utilizing EPO and HBOCs will be beneficial to guide therapy.